Discovery of a New Class of Uracil Derivatives as Potential Mixed Lineage Kinase Domain-like Protein (MLKL) Inhibitors

被引：17

作者：

Cui, Bo ^{[1
,2
]}

Yan, Bo ^{[2
]}

Wang, Kang ^{[2
]}

Li, Lin ^{[2
]}

Chen, She ^{[2
]}

Zhang, Zhiyuan ^{[2
]}

机构：

[1] Beijing Normal Univ, Coll Life Sci, Beijing 100875, Peoples R China

[2] NIBS, Beijing 102206, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 19期

关键词：

HIGHLY POTENT; NECROPTOSIS; PHOSPHORYLATION; MECHANISMS; NECROSIS; RIP1;

D O I：

10.1021/acs.jmedchem.2c00548

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Necroptosis is a form of programmed cell death. Mixed lineage kinase domain-like protein (MLKL) is the necroptosis executor, and it is involved in various diseases such as tissue damage and neurodegeneration-related diseases. Here, we report the development of novel MLKL inhibitors with a uracil nucleus through scaffold morphing from our previously reported xanthine MLKL inhibitor TC13172. After a rational structure- activity relationship study, we obtained the highly potent compounds 56 and 66. Mechanism studies revealed that these compounds partially inhibited MLKL oligomerization and significantly inhibited MLKL translocation to the membrane. Compared with TC13172, 56 and 66 have a different mode of action and, importantly, their reaction rate with glutathione is more than 150-fold lower. This reduction in potential off-target effects and cell toxicity makes this series an attractive starting point for further drug development for MLKL-related disease treatments.

引用

页码：12747 / 12780

页数：34

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